1. Field of the Invention
The present invention relates to topical ophthalmic compositions which act as ocular lubricants and are useful in the treatment of dry eye syndrome and related disorders. These compositions comprise microfine particles of one or more retinoids, and a suitable ophthalmic vehicle.
2. Discussion of Related Art
The problems associated with dry eye syndrome and related eye ailments associated with inadequate lubrication of the eye have been the subject of considerable discussion in the scientific and patent literature. For example, these problems are discussed in U.S. Pat. Nos. 4,131,651; 4,039,662; 3,987,163; 3,920,810; and 3,843,782; and Belgian Patient No. 844,544. The contents of these patents relating to dry eye syndrome and related surface disorders are incorporated herein by reference.
The above-cited patents disclose formulations which are said to relieve the symptoms associated with dry eye syndrome. However, none of these prior art formulations meet all of the important criteria for an effective and long lasting treatment of dry eye syndrome, particularly the moderate to serve keratoconjunctivitis sicca (KCS) patient. These prior art attempts fall into three categories corresponding to their physical state: liquids, anhydrous ointments, and solids. The solids are in the form of ocular inserts which slowly dissolve or erode to provide a thickened tear film. While these have the potential for providing longer term symptomatic relief than liquids, few patients are willing to persist in using them since they are difficult to insert and, once in place, tend to be uncomfortable, frequently themselves causing the foreign body sensation they were meant to treat. Prior liquid and ointment formulations, while giving the sensation of relief, are strictly palliatives without long-term effect.
A further description of the physical manifestations associated with dry eye disorders is seen in a scientific paper presented by Scheffer Chuei-Goong Tseng at the Science Writers Seminar in Ophthalmology, sponsored by Research to Prevent Blindness, Inc., held in Washington, DC, Sept. 30 to Oct. 3, 1984: Tseng, "Topical Vitamin A Treatment for Dry Eye Disorders," pages 1-6 (1984). The Tseng article describes experiments in which an ointment containing Vitamin A is utilized to treat dry eye disorders associated with Sjogrens's Syndrome and Stevens-Johnson Syndrome.
Still further description concerning dry eye disorders is presented in U.S. patent applications Ser. Nos. 700,861 and 695,364 filed Jan. 23, 1985, which are based on International Applications Nos. PCT/US83/00841 and PCT/US83/00840 filed May 25, 1983, respectively; the entire contents of these applications are incorporated herein by reference. These applications are directed to the use of ophthalmic solutions and gels based on polyanionic polymers for the treatment of dry eye disorders. The preparations of the present invention differ from the solutions and gels described in these related applications in that, inter alia, the preparations of the present invention contain microfine particles of one or more retinoids.
Certain retinoids have been previously identified as being useful in the treatment of various ophthalmic disorders. For example, U.S. Pat. No. 3,506,760 discloses oral compositions containing caffeine and beta-carotene (10,000 to 100,000 International Units of Vitamin A activity), and indicates that oral administration of theses compositions provides an effective treatment for night blindness. British Patent Specification No. 1,430,223 discloses topical anti-inflammatory preparations which contain a steroid as a principal active ingredient, along with other ingredients such as antimicrobial and keratolytic agents; retinoic acid is disclosed as a possible keratolytic agent. This patent does not provide any teaching concerning the use of retinoids in ocular lubricant preparations for treating dry eye syndrome and related ophthalmic surface disorders. British Patent Specification No. 1,431,841 discloses the use of ophthalmic-nutritional preparations for the treatment of ophthalmic disorders caused by a Vitamin A deficiency. These preparations contain Vitamin A and other vitamins, and are indicated as being useful when taken orally or applied topically. This reference does not provide any teaching concerning ocular lubricants suitable for the topical treatment of dry eye syndrome. European Patent Application No. EP 0 077 197 A1 discloses the use of retinoic acid in combination with methotrexate to prevent proliferation of remnant lens epithelial cells.
The use of topically applied retinoic acid in the treatment of xerophthalmia, an ophthalmic disorder caused by Vitamin A deficiency and characterized by a dryness of the conjunctiva and cornea, is discussed in the following articles: Sommer, et al., "Topical Retinoic Acid in the Treatment of Corneal Xerophthalmia," American Journal of Ophthalmology, Vol. 86, pages 615-617 (1978); Van Horn, et al., "Topical Retinoic Acid in the Treatment of Experimental Xerophthalmia in the Rabbit," Archives of Ophthalmology, Vol. 99, pages 317-321 (1981); and Pirie, "Effects of Locally Applied Retinoic Acid on Corneal Xerophthalmia in the Rat," Experimental Eye Research, Vol. 25, pages 297-302 (1977). These articles discuss the use of topical retinoic acid therapy in conjunction with systemic administration of Vitamin A to treat xerophthalmia. This discussion does not indicate that topically applied retinoids alone would be effective in the treatment of dry eye disorders and as ocular lubricants. Furthermore, these articles do not offer any solutions to the formulatory problems addressed by the present invention; more specifically, these articles do not disclose or suggest the use of microfine retinoid particles in order to avoid the solubility and crystal irritation problems commonly associated with retinoids.
The use of topically applied retinoids to promote healing of corneal wounds is discussed in the following article: Ubels, et al., "Healing of Experimental Corneal Wounds Treated with Topically Applied Retinoids," American Journal of Ophthalmology, Vol. 95, pages 353-358 (1983). This discussion indicates that the retinoids were dissolved in ethanol and then combined with corn oil. The final formulations are described as solutions which contain "not more than 2% ethanol in corn oil." This article also fails to offer any solutions to the formulation problems addressed by the present invention. Moreover, it is believed that the use of ethanol to solubilize the retinoids and consequent presence of ethanol in the solutions would tend to aggravate most dry eye disorders and counteract any lubricating effect of the solutions.
Three prior art problems associated with ophthalmic compositions containing one or more retinoids have been the poor solubility of retinoids, the instability of pharmaceutical compositions containing these compounds, and the irritation frequently associated with topical application of these compositions to the eye. The present invention is directed to solving these and other problems.